Metabolomics profile of 5649 users and nonusers of hormonal intrauterine devices in Finland

Publisher Copyright: © 2022 The Author(s)Background: Use of hormonal intrauterine devices has grown during the last decades. Although hormonal intrauterine devices act mostly via local effects on the uterus, measurable concentrations of levonorgestrel are absorbed into the systemic circulation. The possible metabolic changes and large-scale biomarker profiles associated with hormonal intrauterine devices have not yet been studied in detail. Objective: To examine through the metabolomics approach the metabolic profile of patients using hormonal intrauterine devices and how this metabolic profile is affected by duration and discontinuation of use. Study Design: The study consisted of cross-sectional analyses of 5 population-based surveys (FINRISK and FinHealth studies), spanning from 1997 to 2017. All fertile-aged participants (18–49 years) in the surveys with available information on hormonal contraceptive use and metabolomics data (n=5649) were included in the study. Altogether, 211 metabolic measures of users of hormonal intrauterine devices (n=1006) were compared with those of nonusers of hormonal contraception (n=4643) via multivariable linear regression models. To allow comparison across multiple measures, association magnitudes were reported in standard deviation units of difference in biomarker concentration compared with the reference group. Results: After adjustment for covariates, levels of 141 metabolites differed in current users of hormonal intrauterine devices compared with nonusers of hormonal contraception (median difference in biomarker concentration, 0.09 standard deviation): lower levels of particle concentration of larger lipoprotein subclasses, triglycerides, cholesterol and derivatives, apolipoproteins A and B, fatty acids, glycoprotein acetyls, and aromatic amino acids. The metabolic pattern of hormonal intrauterine device use did not change according to duration of use. When comparing previous users and never-users of hormonal intrauterine devices, no significant metabolic differences were observed. Conclusion: The use of hormonal intrauterine devices was associated with several moderate metabolic changes previously associated with reduced arterial cardiometabolic risk. The metabolic effects were independent of duration of use of the hormonal intrauterine devices. Moreover, the metabolic profiles were similar after discontinuation of hormonal intrauterine device use and in never-users.Peer reviewe

ANO1 Expression Orchestrates p27Kip1/MCL1-Mediated Signaling in Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that derive from the mucosal epithelium of the upper aerodigestive tract and present high mortality rate. Lack of efficient targeted-therapies and biomarkers towards patients’ stratification are caveats in the disease treatment. Anoctamin 1 (ANO1) gene is amplified in 30% of HNSCC cases. Evidence suggests involvement of ANO1 in proliferation, migration, and evasion of apoptosis; however, the exact mechanisms remain elusive. Aim of this study was to unravel the ANO1-dependent transcriptional programs and expand the existing knowledge of ANO1 contribution to oncogenesis and drug response in HNSCC. We cultured two HNSCC cell lines established from primary tumors harboring amplification and high expression of ANO1 in three-dimensional collagen. Differential expression analysis of ANO1-depleted HNSCC cells demonstrated downregulation of MCL1 and simultaneous upregulation of p27Kip1 expression. Suppressing ANO1 expression led to redistribution of p27Kip1 from the cytoplasm to the nucleus and associated with a cell cycle arrested phenotype. ANO1 silencing or pharmacological inhibition resulted in reduction of cell viability and ANO1 protein levels, as well as suppression of pro-survival BCL2 family proteins. Collectively, these data provide insights of ANO1 involvement in HNSCC carcinogenesis and support the rationale that ANO1 is an actionable drug target

A distinctive DNA methylation pattern in insufficient sleep

Short sleep duration or insomnia may lead to an increased risk of various psychiatric and cardio-metabolic conditions. Since DNA methylation plays a critical role in the regulation of gene expression, studies of differentially methylated positions (DMPs) might be valuable for understanding the mechanisms underlying insomnia. We performed a cross-sectional genome-wide analysis of DNA methylation in relation to self-reported insufficient sleep in individuals from a community-based sample (79 men, aged 39.3 +/- 7.3), and in relation to shift work disorder in an occupational cohort (26 men, aged 44.9 +/- 9.0). The analysis of DNA methylation data revealed that genes corresponding to selected DMPs form a distinctive pathway: "Nervous System Development" (FDR P value <0.05). We found that 78% of the DMPs were hypomethylated in cases in both cohorts, suggesting that insufficient sleep may be associated with loss of DNA methylation. A karyoplot revealed clusters of DMPs at various chromosomal regions, including 12 DMPs on chromosome 17, previously associated with Smith-Magenis syndrome, a rare condition comprising disturbed sleep and inverse circadian rhythm. Our findings give novel insights into the DNA methylation patterns associated with sleep loss, possibly modifying processes related to neuroplasticity and neurodegeneration. Future prospective studies are needed to confirm the observed associations.Peer reviewe

Appetitive traits as behavioural pathways in genetic susceptibility to obesity : a population-based cross-sectional study

The mechanisms through which genes influence body weight are not well understood, but appetite has been implicated as one mediating pathway. Here we use data from two independent population-based Finnish cohorts (4632 adults aged 25-74 years from the DILGOM study and 1231 twin individuals aged 21-26 years from the FinnTwin12 study) to investigate whether two appetitive traits mediate the associations between known obesity-related genetic variants and adiposity. The results from structural equation modelling indicate that the effects of a polygenic risk score (90 obesity-related loci) on measured body mass index and waist circumference are partly mediated through higher levels of uncontrolled eating (beta(indirect) = 0.030-0.032, P <0.001 in DILGOM) and emotional eating (beta(indirect) = 0.020-0.022, P <0.001 in DILGOM and beta(indirect) = 0.013-0.015, P = 0.043-0.044 in FinnTwin12). Our findings suggest that genetic predispositions to obesity may partly exert their effects through appetitive traits reflecting lack of control over eating or eating in response to negative emotions. Obesity prevention and treatment studies should examine the impact of targeting these eating behaviours, especially among individuals having a high genetic predisposition to obesity.Peer reviewe

Eteläpohjalaisten yritysten kasvuprofiilit ja kasvuun vaikuttavat tekijät

Tutkimus on osa ELY-keskuksen EAKR-rahoituksella toteutettua TKI Grow -hanketta. TKI Grow -hankkeen suuressa yritysselvityksessä kartoitettiin eteläpohjalaisten yritysten nykytilaa, vahvuuksia, kasvumahdollisuuksia ja tulevaisuuden tarpeita. Selvityksen toteuttivat Seinäjoen ammattikorkeakoulu, Vaasan yliopisto ja Helsingin yliopiston Ruralia-instituutti. Hankkeessa selvitettiin kyselyn avulla eteläpohjalaisten yritysten vahvuuksia, kasvumahdollisuuksia ja tulevaisuuden tarpeita. Kysely lähetettiin 1005 yritykselle ja tavoitteena oli saada 300 vastausta. Tavoite saavutettiin, vastauksia tuli kaikkiaan 308 ja vastausprosentiksi muodostui 31. Kun aineistosta poistettiin puutteelliset ja päällekkäiset vastaukset, kokonaisaineistoksi muodostui N=273. Seuraavassa esitetään tutkimuksen tuloksia kasvun, kasvutavoitteiden, kasvustrategioiden ja kasvua selittävien asioiden suhteen. Tarkasteltaessa yritysten kasvua jatkuvan kasvun näkökulmasta, oli kolmen vuoden periodilla neljällä prosentilla vastanneista yrityksistä jatkuvaa kasvua vähintään 20 %. Nämä yritykset voidaan luokitella nopean kasvun yrityksiksi. 13 % yrityksistä voitiin luokitella kohtalaisen kasvun yrityksiksi. Näillä vuosittainen kasvu oli välillä 5 - 19 %. 79 prosentilla yrityksistä ei ollut jatkuvaa vuosittaista kasvua. Noin puolet vastanneista yrityksistä on kasvuhakuisia. 13 % vastanneista yrityksistä hakee seuraavan viiden vuoden aikana voimakasta, vähintään 30 prosentin, kasvua liikevaihdossa. 40 % tavoittelee kohtalaista (vähintään 10 %) kasvua tulevaisuudessa. Lisäksi 37 % tavoittelee nykyisen markkina-aseman säilyttämistä ja 9 % ilmoittaa, ettei yrityksellä ole ollenkaan kasvutavoitteita. Kasvustrategioista tärkeimpinä yritykset pitävät nykyisten asiakassuhteiden kehittämistä nykyisillä tuotteilla/palveluilla sekä uusasiakashankintaa. Kasvua haetaan myös uusien palveluiden tai tuotteiden kehittämisellä nykyisille markkinoille. Yrityksen kasvu ei ole kiinni mistään yksittäisestä ominaisuudesta, joskin toteutunut kasvu selittää tulevia kasvutavoitteita. Tuloksista nousevat esiin erityisesti digitalisaatioon ja markkinointiin liittyvät teemat. Kehittämisaktiivisuus ja yhteistyö auttavat yrityksiä menestymään. Raportissa esitellään myös kasvuekosysteemin vahvistamiseksi kehitetty malli korkeakoulujen ja yliopistojen yhteistyön integroinnista ja toimijoiden profiloinnista kasvuyritysten tukemiseksi Etelä-Pohjanmaalla

ANO1 Expression Orchestrates p27Kip1/MCL1-Mediated Signaling in Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that derive from the mucosal epithelium of the upper aerodigestive tract and present high mortality rate. Lack of efficient targeted-therapies and biomarkers towards patients’ stratification are caveats in the disease treatment. Anoctamin 1 (ANO1) gene is amplified in 30% of HNSCC cases. Evidence suggests involvement of ANO1 in proliferation, migration, and evasion of apoptosis; however, the exact mechanisms remain elusive. Aim of this study was to unravel the ANO1-dependent transcriptional programs and expand the existing knowledge of ANO1 contribution to oncogenesis and drug response in HNSCC. We cultured two HNSCC cell lines established from primary tumors harboring amplification and high expression of ANO1 in three-dimensional collagen. Differential expression analysis of ANO1-depleted HNSCC cells demonstrated downregulation of MCL1 and simultaneous upregulation of p27Kip1 expression. Suppressing ANO1 expression led to redistribution of p27Kip1 from the cytoplasm to the nucleus and associated with a cell cycle arrested phenotype. ANO1 silencing or pharmacological inhibition resulted in reduction of cell viability and ANO1 protein levels, as well as suppression of pro-survival BCL2 family proteins. Collectively, these data provide insights of ANO1 involvement in HNSCC carcinogenesis and support the rationale that ANO1 is an actionable drug target. </p

Food neophobia associates with poorer dietary quality, metabolic risk factors, and increased disease outcome risk in population-based cohorts in a metabolomics study

Background: Food neophobia is considered a behavioral trait closely linked to adverse eating patterns and reduced dietary quality, which have been associated with increased risk of obesity and noncommunicable diseases. Objectives: In a cross-sectional and prospective study, we examined how food neophobia is associated with dietary quality, health-related biomarkers, and disease outcome incidence in Finnish and Estonian adult populations. Methods: The study was conducted based on subsamples of the Finnish DIetary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) cohort (n = 2982; age range: 25-74 y) and the Estonian Biobank cohort (n = 1109; age range: 18-83 y). The level of food neophobia was assessed using the Food Neophobia Scale, dietary quality was evaluated using the Baltic Sea Diet Score (BSDS), and biomarker profiles were determined using an NMR metabolomics platform. Disease outcome information was gathered from national health registries. Follow-up data on the NMR-based metabolomic profiles and disease outcomes were available in both populations. Results: Food neophobia associated significantly (adjusted P <0.05) with health-related biomarkers [e.g., omega-3 (n-3) fatty acids, citrate, alpha(1)-acid glycoprotein, HDL, and MUFA] in the Finnish DILGOM cohort. The significant negative association between the severity of food neophobia and omega-3 fatty acids was replicated in all cross-sectional analyses in the Finnish DILGOM and Estonian Biobank cohorts. Furthermore, food neophobia was associated with reduced dietary quality (BSDS: beta: -0.03 +/- 0.006; P = 8.04 x 10(-5)), increased fasting serum insulin (beta: 0.004 +/- 0.0013; P = 5.83 x 10(-3)), and increased risk of type 2 diabetes during the similar to 8-y follow-up (HR: 1.018 +/- 0.007; P = 0.01) in the DILGOM cohort. Conclusions: In the Finnish and Estonian adult populations, food neophobia was associated with adverse alteration of health-related biomarkers and risk factors that have been associated with an increased risk of noncommunicable diseases. We also found that food neophobia associations with omega-3 fatty acids and associated metabolites are mediated through dietary quality independent of body weight.Peer reviewe

Effects of hormonal contraception on systemic metabolism : cross-sectional and longitudinal evidence

Background: Hormonal contraception is commonly used worldwide, but its systemic effects across lipoprotein subclasses, fatty acids, circulating metabolites and cytokines remain poorly understood. Methods: A comprehensive molecular profile (75 metabolic measures and 37 cytokines) was measured for up to 5841 women (age range 24-49 years) from three population-based cohorts. Women using combined oral contraceptive pills (COCPs) or progestin-only contraceptives (POCs) were compared with those who did not use hormonal contraception. Metabolomics profiles were reassessed for 869 women after 6 years to uncover the metabolic effects of starting, stopping and persistently using hormonal contraception. Results: The comprehensive molecular profiling allowed multiple new findings on the metabolic associations with the use of COCPs. They were positively associated with lipoprotein subclasses, including all high-density lipoprotein (HDL) subclasses. The associations with fatty acids and amino acids were strong and variable in direction. COCP use was negatively associated with albumin and positively associated with creatinine and inflammatory markers, including glycoprotein acetyls and several growth factors and interleukins. Our findings also confirmed previous results e.g. for increased circulating triglycerides and HDL cholesterol. Starting COCPs caused similar metabolic changes to those observed cross-sectionally: the changes were maintained in consistent users and normalized in those who stopped using. In contrast, POCs were only weakly associated with metabolic and inflammatory markers. Results were consistent across all cohorts and for different COCP preparations and different types of POC delivery. Conclusions: Use of COCPs causes widespread metabolic and inflammatory effects. However, persistent use does not appear to accumulate the effects over time and the metabolic perturbations are reversed upon discontinuation. POCs have little effect on systemic metabolism and inflammation.Peer reviewe

CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis

Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage-induced initiation of mouse BLBC-like mammary tumors and for survival of HR-defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage-induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNAdamage-induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs. Significance: These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage-induced G2-M checkpoint and proliferative signaling.Peer reviewe

Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy

Correction: Volume: 10 Article Number: 932 DOI: 10.1038/s41467-019-08956-x Published: FEB 20 2019 Accession Number: WOS:000459099300001Elevated MYC expression sensitizes tumor cells to apoptosis but the therapeutic potential of this mechanism remains unclear. We find, in a model of MYC-driven breast cancer, that pharmacological activation of AMPK strongly synergizes with BCL-2/BCL-X-L inhibitors to activate apoptosis. We demonstrate the translational potential of an AMPK and BCL-2/BCL-X-L co-targeting strategy in ex vivo and in vivo models of MYC-high breast cancer. Metformin combined with navitoclax or venetoclax efficiently inhibited tumor growth, conferred survival benefits and induced tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re-growth with presentation of PD-1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by adjuvant metformin+venetoclax+anti-PD-1 treatment to overcome immune escape, led to durable antitumor responses even after drug withdrawal. We demonstrate that pharmacological reactivation of MYC-dependent apoptosis is a powerful antitumor strategy involving both tumor cell depletion and immunosurveillance.Peer reviewe